Project Summary/Abstract Notwithstanding a substantial effort of ?getting to zero?, new HIV infections among people who inject drugs are increasing. Methamphetamine is a primary driver of that increase, as methamphetamine use has been extensively demonstrated to increase both sexual and injection-related HIV transmission. Methamphetamine use is also associated with poor medication adherence, such that people with HIV who use methamphetamine are less likely to be virally suppressed. The most powerful tool for prevention of HIV available today, in addition to aggressive treatment of people living with HIV to ensure viral suppression, is pre-exposure prophylaxis (PrEP) with emtricitabine plus a tenofovir product (e.g. FTC/TAF). PrEP has been extensively demonstrated to reduce HIV infection when taken in sufficient amounts, generally defined as ?4 doses per week. The Centers for Disease Control and other health agencies recommend PrEP for people who inject drugs, yet there has been precious little attention to this population in PrEP clinical trials, implementation studies, and demonstration projects. Two major reasons for this lack of attention are (1) that syringe access programs, where available, are powerful tools to lower HIV transmission by injection, and (2) that people who inject drugs ? and in particular people who use methamphetamine ? are likely to struggle with medication adherence. In the context of expanding methamphetamine use ? as the next wave of the opioid crisis ? and a national effort to eliminate HIV transmission, syringe access programs are unlikely to be sufficient to prevent the remaining infections that occur. In this study, ?PrEP Intervention for people who Inject Methamphetamine? (PRIME), we propose to address the second concern by testing a combined adherence intervention. PRIME is a two-arm trial comparing standardized counseling to video directly-observed treatment with real-time contingency management (VDOT-CM) for adherence to once-daily emtricitabine/tenofovir alafenamide (FTC/TAF) PrEP among people who inject methamphetamine. We will randomize 140 adults who inject methamphetamine, are HIV-negative, and have recently engaged in HIV risk behaviors to VDOT-CM or counseling alone for 24 weeks. Both groups will receive PrEP and counseling to support PrEP adherence; the intervention condition will also receive a mobile phone app that video records daily PrEP use and a nominal contingency management incentive to complete the observed PrEP dosing. We will compare adherence to PrEP in both arms by testing dried blood spots for tenofovir disphosphate (TFV-DP) levels of ? 950 fmol/punch, corresponding to ?4 doses per week. We will assess acceptability of PrEP in this population through qualitative interviews and survey items. Finally, we will compare injection and sexual risk behaviors prior to PrEP to those while on PrEP, to evaluate for risk compensation. Study results will provide critical data for intensive adherence support for PrEP among people who inject methamphetamine, a very high risk population for HIV transmission.